Computational design, molecular properties, ADME, and toxicological analysis of substituted 2,6-diarylidene cyclohexanone analogs as potent pyridoxal kinase inhibitors.

In Silico Pharmacology Pub Date : 2023-03-23 eCollection Date: 2023-01-01 DOI:10.1007/s40203-023-00142-8
Fabian Audu Ugbe, Gideon Adamu Shallangwa, Adamu Uzairu, Ibrahim Abdulkadir
{"title":"Computational design, molecular properties, ADME, and toxicological analysis of substituted 2,6-diarylidene cyclohexanone analogs as potent pyridoxal kinase inhibitors.","authors":"Fabian Audu Ugbe, Gideon Adamu Shallangwa, Adamu Uzairu, Ibrahim Abdulkadir","doi":"10.1007/s40203-023-00142-8","DOIUrl":null,"url":null,"abstract":"<p><p>Leishmaniasis is one of the tropical diseases which affects over 12 million people mainly in the tropical regions of the world and is caused by the leishmanial parasites transmitted by the female sand fly. The lack of vaccines to prevent leishmaniasis, as well as limitations of existing therapies necessitated this study which was focused on a combined virtual docking screening and 3-D QSAR modeling approach to design some diarylidene cyclohexanone analogs, while also performing pharmacokinetic analysis and Molecular Dynamic (MD) simulation to ascertain their drug-ability. As a result, the built 3-D QSAR model was found to satisfy the requirement of a good model with R<sup>2</sup> = 0.9777, SDEC = 0.0593, F-test = 105.028, and Q<sup>2</sup> <sub>LOO</sub> = 0.6592. The template (compound 9, MolDock score =  - 161.064) and all seven newly designed analogs were found to possess higher docking scores than the reference drug (Pentamidine, Moldock score = - 137.827). The results of the pharmacokinetic analysis suggest 9 and the new molecules (9a, b, c, e, and f) as orally bioavailable with good ADME and safe toxicological profiles. These molecules also showed good binding interactions with the receptor (pyridoxal kinase). Additionally, the MD simulation result confirmed the stability of the tested protein-ligand complexes, with an estimated ∆G binding (MM/GBSA) of - 65.2177 kcal/mol and - 58.433 kcal/mol for 9_6K91 and 9a_6K91 respectively. Hence, the new compounds, especially 9a could be considered potential anti-leishmanial inhibitors.</p>","PeriodicalId":13380,"journal":{"name":"In Silico Pharmacology","volume":"11 1","pages":"6"},"PeriodicalIF":0.0000,"publicationDate":"2023-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10033787/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"In Silico Pharmacology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1007/s40203-023-00142-8","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/1/1 0:00:00","PubModel":"eCollection","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

Abstract

Leishmaniasis is one of the tropical diseases which affects over 12 million people mainly in the tropical regions of the world and is caused by the leishmanial parasites transmitted by the female sand fly. The lack of vaccines to prevent leishmaniasis, as well as limitations of existing therapies necessitated this study which was focused on a combined virtual docking screening and 3-D QSAR modeling approach to design some diarylidene cyclohexanone analogs, while also performing pharmacokinetic analysis and Molecular Dynamic (MD) simulation to ascertain their drug-ability. As a result, the built 3-D QSAR model was found to satisfy the requirement of a good model with R2 = 0.9777, SDEC = 0.0593, F-test = 105.028, and Q2 LOO = 0.6592. The template (compound 9, MolDock score =  - 161.064) and all seven newly designed analogs were found to possess higher docking scores than the reference drug (Pentamidine, Moldock score = - 137.827). The results of the pharmacokinetic analysis suggest 9 and the new molecules (9a, b, c, e, and f) as orally bioavailable with good ADME and safe toxicological profiles. These molecules also showed good binding interactions with the receptor (pyridoxal kinase). Additionally, the MD simulation result confirmed the stability of the tested protein-ligand complexes, with an estimated ∆G binding (MM/GBSA) of - 65.2177 kcal/mol and - 58.433 kcal/mol for 9_6K91 and 9a_6K91 respectively. Hence, the new compounds, especially 9a could be considered potential anti-leishmanial inhibitors.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
作为强效吡哆醛激酶抑制剂的 2,6-二芳基环己酮类似物的计算设计、分子特性、ADME 和毒理学分析。
利什曼病是一种热带疾病,主要影响着世界热带地区的 1200 多万人,它是由雌性沙蝇传播的利什曼寄生虫引起的。由于缺乏预防利什曼病的疫苗,以及现有疗法的局限性,本研究采用虚拟对接筛选和三维 QSAR 建模相结合的方法设计了一些二芳基环己酮类似物,同时还进行了药代动力学分析和分子动力学(MD)模拟,以确定它们的可药性。结果发现,建立的三维 QSAR 模型满足良好模型的要求,R2 = 0.9777,SDEC = 0.0593,F 检验 = 105.028,Q2 LOO = 0.6592。与参比药物(喷他脒,Moldock 得分 = - 137.827)相比,模板(化合物 9,MolDock 得分 = - 161.064)和所有 7 个新设计的类似物都具有更高的对接得分。药代动力学分析结果表明,9 和新分子(9a、b、c、e 和 f)具有良好的口服生物可利用性、良好的 ADME 和安全的毒理学特征。这些分子还显示出与受体(吡哆醛激酶)良好的结合相互作用。此外,MD 模拟结果证实了所测试的蛋白质配体复合物的稳定性,9_6K91 和 9a_6K91 的ΔG 结合力(MM/GBSA)估计值分别为 - 65.2177 kcal/mol 和 - 58.433 kcal/mol。因此,这些新化合物,尤其是 9a 可被视为潜在的抗利什曼病菌抑制剂。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
自引率
0.00%
发文量
0
期刊最新文献
Predicting phase-I metabolism of piceatannol: an in silico study Exploring isoindolin-1-ones as potential CDK7 inhibitors using cheminformatic tools Investigation of alpha amylase inhibitors from Bidens pilosa L. by in silico and in vitro studies Network pharmacology reveals the potential of Dolastatin 16 as a diabetic wound healing agent. RND pump inhibition: in-silico and in-vitro study by Eugenol on clinical strain of E. coli and P. aeruginosa.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1